Abstract 11091: Failure of Right Ventricular Adaptation to Pressure Overload Due to a Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics
Bibliographic record
Abstract
Introduction: Interindividual heterogeneity in the ability of the right ventricular (RV) to adapt to pressure overload in pulmonary hypertension (PH) is likely influenced by genetic determinants. We took advantage of strain-dependent, maladaptive RV remodeling in Fischer compared to Sprague-Dawley (SD) rats to define the molecular and genetic mechanisms that predispose to development of RV failure in PH. Methods/Results: In the SU5416/hypoxia(SUHx) PH model, Fischer rats exhibited RV failure and 100% mortality by 5-weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (p<0.0001). In vivo oxidative metabolism, assessed by [ 11 C]acetate PET, was increased in Fischer rats at 4 weeks (p<0.05), associated with impaired RV efficiency compared to SD (work metabolic index: 58±12 vs 102±20 mmHg·mL/cm 2 , respectively; p<0.001), but no differences were observed in mitochondrial complex activity in permeabilized RV cardiac fibers. Adenylate Kinase 1 (AK1) was among the top ten differentially expressed genes between Fischer and SD rats by unbiased transcriptomic analysis, with markedly lower expression in the RV of Fischer rats (FC:3.36, P<0.05). Profound AK1 deficiency was confirmed by proteomics and validated by Western blotting (>10-fold reduction, P<0.001). Fischer rats also exhibited evidence of hemolysis, recapitulating the hemolytic phenotype seen in patients with rare AK1 coding region mutations. While whole genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region. AK1 levels were also reduced in the RV of PH patients with decompensated RV function and right heart failure. Conclusion: Fischer rats with AK1 deficiency have inefficient energetics likely related to reduced ATP shuttling from the mitochondria to the contractile fibers, which represents a novel mechanism for RV failure in response to chronic increases in afterload.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".